Antibody Cross-Reactivity Between Zika Virus, Kedougou Virus, and Spondweni Virus

Zika virus (ZIKV), dengue virus (DENV), Kedougou virus (KEDV), and Spondweni virus (SPOV) are closely-related, mosquito-borne flaviviruses. It is well-established that ZIKV and DENV both cause fever, rash, and joint pain, in addition to more severe disease states such as microcephaly and hemorrhagic fever, respectively. However, little is known about KEDV or SPOV infections because they have not yet caused large human outbreaks. Given that cross- reactive antibodies between ZIKV and DENV complicate serodiagnostic tests in regions where both viruses circulate, it is crucial to understand and develop serological applications for other flaviviruses, such as KEDV and SPOV, which are even more closely related to ZIKV than DENV is. In addition, identifying a molecular basis for the cross-neutralization of ZIKV, KEDV, and SPOV can help inform the development of neutralizing antibodies and broadly protective vaccines. The objective of this project was to assess the neutralization of ZIKV (strain H/PF/ 2013), KEDV (D14701), and SPOV (SA Ar 94) by mouse polyclonal immune sera (anti-ZIKV, anti-KEDV, and anti-SPOV) and human convalescent sera (ZIKV-immune and DENV-immune). Another goal was to determine whether a panel of monoclonal antibodies (mAbs), specific to particular epitopes on the flavivirus E protein (domain I, domain II, domain III, fusion loop), broadly neutralized ZIKV, KEDV, and SPOV. Here, we found that anti-ZIKV mouse immune sera cross-neutralized KEDV and SPOV, though anti-KEDV and anti-SPOV sera did not cross- neutralize ZIKV (FRNT≤25). We observed that several mouse and human mAbs targeting the fusion loop bound ZIKV, KEDV, and SPOV. However, these fusion loop mAbs neutralized SPOV but not ZIKV, suggesting that virion maturation state could impact cross-neutralization. In addition, we identified two mAbs—G9E and EDEC8—that cross-neutralized both ZIKV and SPOV by targeting the E protein cross-dimer interface, including domains I and II. These findings allow for subsequent studies on the cross-neutralization of ZIKV, KEDV, and SPOV by an expanded panel of ZIKV-immune and DENV-immune human convalescent sera samples, as well as other mAbs that cross-neutralize these viruses. This would facilitate both vaccine design and serodiagnostics in the event that a new flavivirus emerges in ZIKV/DENV co-endemic areas.Bachelor of Scienc